X-Message-Number: 30840
Date: Mon, 30 Jun 2008 10:24:54 -0700 (PDT)
From: 
Subject: Reversal of aging by NFkappaB blockade

[At the very least, in addition to vitamin D depletion, NFkappaB
upregulation seems to be partly responsible for increases in cancer risk
with age.]

Cell Cycle. 2008 Mar;7(5):556-9. Epub 2007 Dec 26.
Reversal of aging by NFkappaB blockade.
    Adler AS, Kawahara TL, Segal E, Chang HY. Program in Epithelial Biology
and Cancer Biology Program, Stanford University School of Medicine,
Stanford, California 94305, USA.
    Genetic studies in model organisms such as yeast, worms, flies, and mice
leading to lifespan extension suggest that longevity is subject to
regulation. In addition, various system-wide interventions in old animals
can reverse features of aging. To better understand these processes, much
effort has been put into the study of aging on a molecular level. In
particular,
genome-wide microarray analysis of differently aged individual organisms or
tissues has been used to track the global expression changes that occur
during normal aging. Although these studies consistently implicate specific
pathways in aging processes, there is little conservation between the
individual genes that change. To circumvent this problem, we have recently
developed a novel computational approach to discover transcription factors
that may be responsible for driving global expression changes with age. We
identified the transcription factor NFkappaB as a candidate activator of
aging-related transcriptional changes in multiple human and mouse tissues.
Genetic blockade of NFkappaB in the skin of chronologically aged mice
reversed the global gene expression program and tissue characteristics to
those of young mice, demonstrating for the first time that disruption of a
single gene is sufficient to reverse features of aging, at least for the
short-term.
PMID: 18256548

Genes Dev. 2007 Dec 15;21(24):3244-57. Epub 2007 Nov 30.
Motif module map reveals enforcement of aging by continual NF-kappaB
activity.
    Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY. Program in
Epithelial Biology and Cancer Biology Program, Stanford University
School of Medicine, Stanford, California 94305, USA.
    Aging is characterized by specific alterations in gene expression, but
their underlying mechanisms and functional consequences are not well
understood. Here we develop a systematic approach to identify combinatorial
cis-regulatory motifs that drive age-dependent gene expression across
different tissues and organisms. Integrated analysis of 365 microarrays
spanning nine tissue types predicted fourteen motifs as major regulators of
age-dependent gene expression in human and mouse. The motif most strongly
associated with
aging was that of the transcription factor NF-kappaB. Inducible genetic
blockade of NF-kappaB for 2 wk in the epidermis of chronologically aged mice
reverted the tissue characteristics and global gene expression programs to
those of young mice. Age-specific NF-kappaB blockade and orthogonal cell
cycle interventions revealed that NF-kappaB controls cell cycle exit and
gene expression signature of aging in parallel but not sequential pathways.
These results identify a conserved network of regulatory pathways underlying
mammalian aging and show that NF-kappaB is continually required to enforce
many features of aging in a tissue-specific manner.
PMID: 18055696

J Mol Biol. 2008 Jan 18;375(3):637-49. Epub 2007 Oct 10.
Prevention of cardiac hypertrophy and heart failure by silencing of
NF-kappaB.
    Gupta S, Young D, Maitra RK, Gupta A, Popovic ZB, Yong SL, Mahajan A,
Wang Q, Sen S. Department of Molecular Cardiology, Lerner Research
Institute, NB50, The Cleveland Clinic Foundation, 9500 Euclid Ave.,
Cleveland, OH 44195, USA.
    Activation of the nuclear factor (NF)-kappaB signaling pathway may be
associated with the development of cardiac hypertrophy and its transition to
heart failure (HF). The transgenic Myo-Tg mouse develops hypertrophy and HF
as a result of overexpression of myotrophin in the heart associated with
an elevated level of NF-kappaB activity. Using this mouse model and an
NF-kappaB-targeted gene array, we first determined the components of
NF-kappaB signaling cascade and the NF-kappaB-linked genes that are
expressed during the progression to cardiac hypertrophy and HF. Second, we
explored the effects of inhibition of NF-kappaB signaling events by using a
gene
knockdown approach: RNA interference through delivery of a short hairpin RNA
against NF-kappaB p65 using a lentiviral vector (L-sh-p65). When the short
hairpin RNA was delivered directly into the hearts of 10-week-old Myo-Tg
mice, there was a significant regression of cardiac hypertrophy, associated
with a
significant reduction in NF-kappaB activation and atrial natriuretic factor
expression. Our data suggest, for the first time, that inhibition of
NF-kappaB using direct gene delivery of sh-p65 RNA results in regression of
cardiac hypertrophy. These data validate NF-kappaB as a therapeutic target
to prevent hypertrophy/HF.
PMID: 18037434

[There are plenty of  NFkappab inhibitors in fruits.]

J Agric Food Chem. 2007 Nov 14;55(23):9678-84. Epub 2007 Oct 19.
Myricetin down-regulates phorbol ester-induced cyclooxygenase-2 expression
in mouse epidermal cells by blocking activation of nuclear factor kappa B.
    Lee KM, Kang NJ, Han JH, Lee KW, Lee HJ. Department of Agricultural
Biotechnology and Center for Agricultural Biomaterials, Seoul National
University, Seoul 151-921, Republic of Korea.
    Abnormal expression of cyclooxygenase-2 (COX-2) has been implicated in
the development of cancer. There are multiple lines of evidence that red
wine exerts chemopreventive effects, and 3,5,4'-trihydroxy- trans-stilbene
(resveratrol), which is a non-flavonoid polyphenol found in red wine, has
been reported to be a natural chemopreventive agent. However, other
phytochemicals might contribute to the cancer-preventive activities of red
wine, and the flavonol content of red wines is about 30 times higher than
that of resveratrol. Here we report that 3,3',4',5,5',7-hexahydroxyflavone
(myricetin), one of the major flavonols in red wine, inhibits
12-O-tetradecanoylphorbol-13-acetate (phorbol ester)-induced COX-2
expression in JB6 P+ mouse epidermal (JB6 P+) cells by suppressing
activation of nuclear factor kappa B (NF-kappaB). Myricetin at 10 and 20
microM inhibited phorbol
ester-induced upregulation of COX-2 protein, while resveratrol at the same
concentration did not exert significant effects. The phorbol ester-induced
production of prostaglandin E 2 was also attenuated by myricetin treatment.
Myricetin inhibited both COX-2 and NF-kappaB transactivation in phorbol
ester-treated JB6 P+ cells, as determined using a luciferase assay.
Myricetin blocked the phorbol ester-stimulated DNA binding activity of
NF-kappaB, as determined using an electrophoretic mobility shift assay.
Moreover, TPCK (N-tosyl-l-phenylalanine chloromethyl ketone), a NF-kappaB
inhibitor,
significantly attenuated COX-2 expression and NF-kappaB promoter activity in
phorbol ester-treated JB6 P+ cells. In addition, red wine extract inhibited
phorbol ester-induced COX-2 expression and NF-kappaB transactivation in JB6
P+ cells. Collectively, these data suggest that myricetin contributes
to the chemopreventive effects of red wine through inhibition of COX-2
expression by blocking the activation of NF-kappaB.
PMID: 17944529

Anticancer Res. 2007 Mar-Apr;27(2):937-48.
Inhibition of cancer cell proliferation and suppression of TNF-induced
activation of NFkappaB by edible berry juice.
    Boivin D, Blanchette M, Barrette S, Moghrabi A, B liveau R. Laboratoire
de M decine Mol culaire, H pital Ste-Justine-UQAM, Centre de Canc rologie
Charles-Bruneau, Centre de Recherche de l'H pital Sainte-Justine, 3175,
Chemin C te-Sainte-Catherine, Montr al, Qu bec, Canada.
    BACKGROUND: Berries contain several phytochemicals, such as phenolic
acids, proanthocyanidins, anthocyanins and other flavonoids. There has been
growing interest in a variety of potential chemopreventive activities of
edible berries. The potential chemopreventive activity of a variety of small
berries cultivated or collected in the province of Qu bec, Canada were
evaluated here. MATERIALS AND METHODS: Strawberry, raspberry, black currant,
red currant, white currant, gooseberry, high-bush blueberry, low-bush
blueberry, velvet leaf blueberry, serviceberry, blackberry, black
chokeberry, sea buckthorn and cranberry were evaluated for antioxidant
capacity, anti-proliferative activity, anti-inflammatory activity, induction
of apoptosis and cell cycle arrest. RESULTS: The growth of various cancer
cell lines, including those of stomach, prostate, intestine and breast, was
strongly inhibited by raspberry, black currant, white currant, gooseberry,
velvet leaf blueberry, low-bush blueberry, sea buckthorn and cranberry
juice, but not (or only slightly) by strawberry, high-bush blueberry,
serviceberry, red currant, or blackberry juice. No correlation was found
between the anti-proliferative activity of berry juices and their
antioxidant capacity (p > 0.05). The inhibition of cancer cell proliferation
by berry juices did not involve caspase-dependent apoptosis, but appeared to
involve cell-cycle arrest, as evidenced by down-regulation of the expression
of cdk4, cdk6, cyclin D1 and cyclin D3. Of the 13 berries tested, juice of 6
significantly inhibited the TNF-induced activation of COX-2 expression and
activation of the nuclear transcription factor NFkappaB. CONCLUSION: These
results illustrate that berry juices have striking differences in their
potential chemopreventive activity and that the inclusion of a variety of
berries in the diet might be useful for preventing the development of
tumors.
PMID: 17465224

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